The present invention relates to a process for preparing sustained release micelle employing a conjugate of anticancer drug and biodegradable polymer, more specifically, to a process for preparing sustained release micelle by conjugating a biodegradable polymer to a drug such as anticancer agent, and a sustained release micelle prepared by the process.
In general, polymers used for drug delivery are required to be biosynthetic or biodegradable. Representative polymers satisfying these requirements are aliphatic polyesters containing polyester bonds, which are under FDA approval and used widely as a drug delivery carrier or a suture. Examples of the aliphatic polyesters include polylactic acid(PLA), polyglycolic acid(PGA), poly(D,L-lactic-co-glycolic acid)(PLGA), poly(caprolactone), poly(valerolactone), poly(hydroxybutyrate) and poly(hydroxyvalerate). Among the aliphatic polyesters, PLGA, in particular, have been practically employed as biodegradable polymers with a variety of degradation time by controlling the contents of lactic acid and glycolic acid monomers, or by modifying the process of polymerization.
Since the biodegradable polymers are degraded in a certain period of time, they are not harmful to the human body. For example, a polymer such as PLGA is degraded into non-toxic lactic acid and glycolic acid in the body. Therefore, drug delivery carriers made of biodegradable polymers can be applied in the sustained release of drugs. In particular, drugs which should be administered periodically for a long period of time to keep a constant level in blood can be loaded to the drug delivery carrier, whereby the drugs are released in a sustained manner with the degradation of polymer matrices, therefore, such a sustained release mechanism can be applied in a variety of drug formulations.
Drug delivery carriers employed in the sustained release include microspheres, nanoparticles, and micelles. The size of microspheres range from tens to hundreds of micrometers, nanoparticles around hundreds of nanometers, and micelles about one hundred nanometers. Microsphere preparations are used for subcutaneous intramuscular injections to sustain the release of proteins or drugs. Nanoparticle preparations, mainly used for intravenous injection, are employed for the sustained release of drugs, and for the passive targeting of anticancer drugs to solid tumors. Micelle preparations also can be used for similar purposes described above. When nanoparticle or micelle preparations of anticancer drugs are administered, the size of particles ranging from tens to hundreds of nanometers let them penetrate into tumor tissues across the wall of blood vessel which have loosened cell contact, but would not let them penetrate into normal tissues across the wall of blood vessel which have tight cell contact, therefore, the lack of specificity of anticancer drugs can be successfully overcome due to the structural difference.
Meanwhile, one of crucial problems in conventional drug delivery systems is that drugs cannot be released in a sustained manner. That is, conventional drug delivery systems release high amount of drug at the early stage of administration by way of simple diffusion of drug on the surface of carrier, meanwhile, the amount of released drug is decreasing with time, which plays a detrimental role in maintaining a constant level of drug in blood. Furthermore, in order to load drugs into the carrier sufficiently, large amount of drugs are required, which eventually causes significant drug loss usually up to 50% in the course of loading (that is, in the preparation or formulation). In this respect, much research effort is being devoted to the improvement of loading efficiency.
Drugs such as doxorubicin, adriamycin, cisplatin, taxol, and 5-fluorouracil are being widely used in chemotherapies for the treatment of cancer. However, the said anticancer drugs cannot be administered with a large amount due to severe side effects, and give pains to the patients even with as little as effective concentration. Such side effects are mainly caused by the lack of specificity of anticancer drugs, that is, the anticancer drugs not only kill cancer cells but also inhibit normal cell growth and eventually lead to necrosis of normal cells.
Therefore, if an anticancer drug can destroy cancerous cells selectively, it would be administered with a high amount, and effectively applied in the treatment. To achieve this goal, the techniques of drug targeting to cancer cells have been commonly used until now, in which therapeutic agents are linked to a receptor which has a high affinity to an antigen specifically expressed on the cancer cells(see: Minko, T. et al., J. Control. Rel., 54:223-233, 1998; Colin de Verdiere, A. et al., Cancer Chemother. Pharmacol., 33:504-508, 1994).
However, it has been found that repetitive administration of such agents activate an excretory pump which facilitates the excretion of anticancer agents absorbed into cells, resulting in the failure of maintaining the effective level of anticancer agents in the cytoplasm and the failure of exerting anticancer activity. In this regard, many efforts to overcome such problems have been made, however, no remarkable results were attained.
Under the circumstances, there are strong reasons for exploring and developing a sustained release preparation without untoward effects.
The present inventors have made an effort to reduce the side effects due to the lack of specificity of conventional anticancer agents and to prepare sustained release intravenous injectable formulations, and found that the sustained release micelle prepared by conjugating a biodegradable polymer to a drug such as anticancer agent can be practically applied in anticancer therapy in an efficient manner, by loading a high amount of drug while controlling the release rate of drug.
A primary object of the present invention is, therefore, to provide a process for preparing a sustained release micelle employing a conjugate of biodegradable polymer and drug.
The other object of the invention is to provide a sustained release micelle prepared by the process.